Diabetic peripheral neuropathy (DPN) is characterized by altered chemical, thermal and mechanical sensitivities. Since Transient Receptor Potential (TRP) family of ion channels transduces chemical, thermal and mechanical sensation, it is likely that TRP Vanilloid 1 (TRPV1) and TRP Vanilloid 4 (TRPV4) are involved DPN. In this study, we will use streptozotocin-induced diabetic (SD) rats as a model for type1 diabetes mellitus (T1DM) and Zucker diabetic fatty (ZDF) rats as a model for type 2 diabetes mellitus (T2DM). The expression and function of nociceptive ion channels TRPV1 and TRPV4 will be studied. In preliminary experiments, using mouse models of diabetes, we have found that diabetic mice exhibit an initial phase of thermal hyperalgesia followed by a phase of thermal hypoalgesia. The mechanisms underlying these phenotypes will help us understand the hypersensitivity and the marked sensory loss observed in patients with diabetes. In Aim 1, we will determine the expression and function of TRPV1 and TRPV4 in peripheral nerve terminals and the DRG neuronal cell bodies. In spite of sensory loss as a result of nerve terminal degeneration, some patients experience burning pain sensation. This suggests that peripheral sensitization is not responsible for the pain, and central sensitization is more likely to be involved at spinal and supraspinal sites. In the second aim, we will determine the expression and function of TRPV1 and TRPV4 at the spinal dorsal horn and determine their role in the modulation of synaptic transmission. Then, we will determine whether targeting TRP channels in the spinal cord can relieve hypersensitivity. DPN also affects internal organs and blood vessels innervated by sensory nerves mediating efferent nonsensory functions. In the third aim, we will determine the expression and function of TRPV1 and TRPV4 in blood vessels and examine the functional consequence(s) by studying the changes in the vascular tone and endothelial cell functions. Findings from this study will increase our understanding how sensory and nonsensory functions of TRPV1 and TRPV4 impact the disease process. The complications of DPN can be prevented/delayed by maintaining normal glucose levels and expression and function of TRP channels by therapeutic interventions.